Modeling the Fast Gating Mechanism in the ClC-0 Chloride Channel

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• 作者：Mary H. Cheng ; Artem B. Mamonov ; J. Warren Dukes ; Rob D. Coalson
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：May 31, 2007
• 年：2007
• 卷：111
• 期：21
• 页码：5956 - 5965
• 全文大小：144K
• 年卷期：v.111,no.21(May 31, 2007)
• ISSN：1520-5207

文摘

A simplified three-dimensional model ClC-0 chloride channel is constructed to couple the permeation of Cl^-ions to the motion of a glutamate side chain that acts as the putative fast gate in the ClC-0 channel. The gateis treated as a single spherical particle attached by a rod to a pivot point. This particle moves in a one-dimensional arc under the influence of a bistable potential, which mimics the isomerization process by whichthe glutamate side chain moves from an open state (not blocking the channel pore) to a closed state (blockingthe channel pore, at a position which also acts as a binding site for Cl^- ions moving through the channel). Adynamic Monte Carlo (DMC) technique is utilized to perform Brownian dynamics simulations to investigatethe dependence of the gate closing rate on both internal and external chloride concentration and the gatecharge as well. To accelerate the simulation of gate closing to a time scale that can be accommodated withcurrent methodology and computer power, namely, microseconds, parameters that govern the motion of thebare gate (i.e., in the absence of coupling to the permeating ions) are chosen appropriately. Our simulationresults are in qualitative agreement with experimental observations and consistent with the "foot-in-the-door" mechanism (Chen et al. J. Gen. Physiol. 2003, 122, 641; Chen and Miller J. Gen. Physiol. 1996, 108,237), although the absolute time scale of gate closing in the real channel is much longer (millisecond timescale). A simple model based on the fractional occupation probability of the Cl^- binding site that is ultimatelyblocked by the fast gate suggests straightforward scalability of simulation results for the model channelconsidered herein to experimentally realistic time scales.